The blood-brain barrier (BBB) damage and dysfunction is well-recognized as a major hallmark of ischemic stroke. As a major component of the BBB, brain microvascular endothelial cells (BMECs), together with the tight junctions (TJs) between BMECs, play a dominant role in modulating BBB integrity and paracellular permeability. Extensive studies have shown that breakdown of the BBB contributes to cerebral inflammatory responses, edema, hemorrhagic transformation, and eventual neuronal loss in cerebral ischemia. Thus, it is important to identify mechanisms by which BBB integrity and function can be compromised in ischemic stroke. Krppel-like factors (KLFs) are members of the zinc finger family of transcription factors and consist of 17 members that have been shown to play key roles in cellular growth and differentiation. Recent studies have documented that KLFs are implicated in developmental and pathological vascular processes. However, the function of the KLF family in the cerebral vasculature is largely unexplored. KLF11 is a unique diabetes- associated KLF transcription factor among 17 KLF family members and highly expresses in vascular endothelium. Mutations in the KLF11 gene result in Maturity Onset Diabetes of the Young 7 (MODY7), and are closely associated with human type 2 diabetes mellitus, a major risk factor for stroke. Previously, we reported that peroxisome proliferator-activated receptor ?-mediated cerebral vascular protection during ischemic insults needs recruitment of KLF11 as its critical co-activator. However, the functional significance and mechanisms of KLF11 itself in regulating cerebrovascular pathogenesis are totally unknown in ischemic stroke. In our recent preliminary studies, we have shown that KLF11 expression is significantly decreased in the cerebral vasculature, and also in cultured BMECs after in vivo and in vitro ischemic stimuli. Of note, EC- selective KLF11 transgenic mice display reduced BBB leakage in ischemic brains, whereas KLF11 genetic deficiency results in increased BBB permeability and larger brain infarction in mice after middle cerebral artery occlusion (MCAO). Mechanistically, we found several potential KLF11 binding sites in the promoter region of selective endothelial tight junctions, and genetic deletion of KLF11 in mice significantly reduced cerebral expression of Claudin 5 and ZO-1 mRNAs as well as increased leukocyte-endothelial rolling and adhesion in the vascular wall. Moreover, we also demonstrated that gain-of-KLF11 function by adenovirus can significantly inhibit BMEC death after exposure to Oxygen Glucose Deprivation (OGD). These findings have provided the basis for our Central Hypothesis that endothelial KLF11 functions as a novel BBB stabilizer and its reduction contributes to BBB dysfunction and brain injury after ischemic stroke. Three aims will be performed in this proposal. Aim 1: Define the role of KLF11 in BBB dysfunction and brain injury after ischemic stroke; Aim 2: Define the molecular mechanisms of KLF11 in regulating ischemia-induced BBB dysfunction; Aim 3: Define if activation of KLF11 by upstream signaling regulates post-ischemic BBB dysfunction.